World Health Organization has named major depression as the fourth overall cause of disability worldwide. This reflects not only the mental anguish of depression, but also susceptibility to physical illnesses that double the patients' mortality at any age. We reported that over 10% of premenopausal women with major depression have osteoporosis, and another 15% have osteopenia. Both conditions increase the risk of fracture. We have replicated this finding in a larger study that included 73 premenopausal women with major depression and 73 individually controls matched individually to each patient for age, smoking history, height, and weight. Given the incidence of major depression in the general population, both of our studies predict that over 350,000 premenopausal women in the United States today have unrecognized osteoporosis secondary to major depression. Osteoporosis is generally a silent disease until the first clinical event so that many of these patients will not be diagnosed until after a fracture. We have currently instituted double blind, placebo controlled trial of alendronate, a bisphosphonate capable of reversing bone loss and of producing a 2-3% increase in bone density per year, enough t very significantly reduce the risk of fracture. In hormonal samples measured every one hour for 24 hours in each of our 73 patients and controls, we found that those who had lost bone had increased plasma levels of cortisol, and that there was a positive correlation with plasma cortisol levels and the magnitude of bone loss. In addition to premature osteoporosis, patients with major depression have a doubling of the rate of premature coronary artery disease. We postulated that because of the neuroendocrine milieu of major depression, patients with depressive disorder would be prone to insulin resistance, a condition that has a pronounced effect on increasing the rate of coronary artery disease. In a group of 62 women with major depression an 62 controls matched for gender, age, and body mass index. We found that patients with major depression were indeed insulin resistance. We also found that our patients with depressive illness had significantly higher levels of plasma glucose and plasma insulin, the latter as a compensatory response to their insulin resistance. High insulin levels are highly pathogenic. Insulin stimulates the sympathetic nervous system, the relapse of proinflammatory mediator, the release of clotting factors that increase coagulation, and the release of compounds that inhibit fibrinolysis. Indeed we found that patients with major depression have a significant increase in factor VIII, known to significantly increase the incidence of clinically-relevant thrombosis. We also found that drug free patients with extremely severe melancholic depression have increased basal blood pressures and pulse rates, and significant, continuous increases in plasma and CSF NE measured hourly for 30 hour via indwelling venous and lumbar drains. These abnormalities resolved after electroconvulsive treatment of their depressions. We found that a less severely depressed group of drug free patients with melancholic depression had significant increases n total body norepinephrine and pulse rates at baseline and in response to psychological an physiological stressors. Taken together, our depressed patients seem t have a syndrome driven by excess cortisol and norepinephrine that significantly reduces bone mineral density and promotes insulin resistance (and its squall): increased clotting and antifibrinolytic factors. This adverse neuroendocrine and autonomic milieu in thus highly clinically relevant: premature osteoporosis and osteopenia; hypertension and profound increases in sympathetic outflow; insulin resistance and pathological changes in homeostatic mediators. The goal of our work is to find improved means for the early detection, treatment, or prevention of the premature osteoporosis and coronary artery disease of depressive illness.